Abstract

The RIG‐I‐like receptors (RLRs), RIG‐I (retinoic acid inducible gene 1), MDA5 (melanoma differentiation‐associated gene 5)
and LGP2 (laboratory of genetics and physiology 2) play an essential role in sensing viral infection and initiating interferon‐mediated
antiviral immune response. RLRs share similar domain architecture to support specific detection of viral RNA (ribonucleic
acid). RIG‐I has an auto‐inhibitory conformation and upon binding of RNA ligand undergoes conformational changes to expose
N‐terminal CARDs (caspase activation and recruitment domains) for interaction with the adaptor protein MAVS (mitochondrial
antiviral‐signalling protein) for signalling. MDA5 adopts an open but inactive conformation and is able to oligomerise on
long RNA duplexes to bring its CARDs into close proximity to MAVS. The downstream signalling cascade up‐regulates the type
I interferon expression. Post‐translational modifications, alternative splicing and translational variants as well as several
regulatory proteins play important roles in the regulation of RLRs signalling. Although robust activation of RLRs is essential
for clearance of viral infection, uncontrolled activation of RLR signalling could potentially trigger or exacerbate pre‐existing
autoimmune conditions.

Key Concepts

RLRs undergo conformational changes leading to activation when bound to viral RNA

RLRs relay signal to a common signalling adaptor MAVS (mitochondrial antiviral‐signalling protein) leading to activation of
transcription factors promoting the expression of interferons and pro‐inflammatory cytokines which reduces initial viral replication
and spread

RLRs are tightly regulated by various proteins and post‐translational modifications to prevent undesired auto‐activation

Diao F, Li S, Tian Y, et al. (2007) Negative regulation of MDA5‐ but not RIG‐I‐mediated innate antiviral signaling by the dihydroxyacetone kinase. Proceedings of the National Academy of Sciences of the United States of America 104: 11706–11711.

Saito T, Hirai R, Loo Y‐M, et al. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG‐I and LGP2. Proceedings of the National Academy of Sciences of the United States of America 104: 582–587.